NMDA receptor antagonist 4 [1607589-56-9]

NMDA receptor antagonist 4 (IIc) is an uncompetitive, voltage-dependent, orally active NMDAR blocker with an IC₅₀ of 1.93 μM. It shows positive predicted blood-brain-barrier (BBB) permeability and can be used in Alzheimer's disease research[1].

NMDA receptor antagonist 4 (IIc) competitively interacts with the endogenous blocker Mg2+ and exhibits membrane potential dependence in the NMDAR channel [1]. It shows high metabolic stability in human and mouse liver microsomes and demonstrates hERG safety without observable cytotoxicity [1]. In a cell cytotoxicity assay using Neuro2A cells, at concentrations of 1, 10, and 100 μM over 24 hours, it did not show cytotoxicity at the highest concentration tested (100 μM) [1].

NMDA receptor antagonist 4 (IIc) exhibited significant neuroprotective effects in vitro and in vivo at 0-10 μM, reducing motor deficits and protecting against Aβ toxin-induced neuronal dysfunction. Orally administered at 5 mg/kg/day for four weeks, it enhanced cell survival and synaptic function in Alzheimer's disease models, attributed to activation of the Fyn-GluN2B-CREB signaling pathway and prevention of synaptic NMDARs internalization. In C. elegans models (N2 wild-type, CL2006, CL2122, CL2355), it ameliorated defective locomotion in CL2006 nematodes and improved chemotaxis in CL2355 nematodes affected by Aβ expression. In six-month-old female 5XFAD mice, the treatment regimen enhanced working memory function, restored GluN2A and postsynaptic density protein (PSD) 95 expression, increased Fyn and GluN2B phosphorylation, significantly raised p-CREB protein levels in the nucleus, and reverted calbindin D-28K protein levels.